Abstract
There is an increasing demand for “drug-free” treatment options for pain and systemic inflammatory diseases. 1 In the United States alone, one in three people are affected by chronic pain. Approximately 25% of the population suffer from some form of musculoskeletal disease, such as rheumatoid arthritis, back pain, or fibromyalgia. 2 These conditions often occur in association with inflammatory comorbidities such as hypertension and diabetes. Despite the advances in the development of anti-inflammatory and analgesic drugs with decreased side effects, patients and health care providers are seeking alternative approaches to effectively manage pain and systemic inflammation. 1 Hence, it is not coincidence that the market for photobiomodulation (PBM) devices, with emphasis on wearable technologies, is growing and contributing to a significant share of the total medical laser market size, which is predicted to reach ∼$ 16 billion USD by 2026. 3
As part of this trend, protocols that aim to operate on the body at a systemic level are being popularized among clinicians and patients. These protocols, pioneered by the intravascular laser irradiation of blood (ILIB) method, aspire to provide an adjuvant treatment that can boost the immune system, decrease inflammation, control pain, and improve the outcomes of some musculoskeletal disorders and systemic inflammatory diseases. 4 Even though the beneficial systemic effects of intravascular irradiation have been studied and described for years, 5 –7 its underlying mechanisms of action are not well understood. As a result, the adoption of this therapy is still controversial. 8
Although there is skepticism about the effects of intravascular irradiation, the use of empirical protocols is widespread, particularly with the popularization of portable lasers and LEDs (light emitting diodes) with associated wearable devices. Pushed by patients' and caregivers' demands, technologies have evolved in recent years, advancing intravascular irradiation techniques from invasive procedures involving implantation of a light deliverable device 9 to current noninvasive protocols of extravascular transcutaneous 10 and transmucosal irradiations. 11 Although several basic and translational investigations have confirmed that red and infrared light sources can penetrate the tissues and cause lymphocytes to proliferate, activate, secrete anti-inflammatory cytokines, and release nitric oxide, 12 clinical trials focusing on the outcomes of vascular invasive and noninvasive PBM are limited in the English literature. Moreover, authors are almost unanimous in indicating a need for mechanistic studies, deeper evaluation of optimal doses, and definition of application protocols. 13,14
Recently, the effectiveness of ILIB as an adjuvant therapy for the treatment of chronic systemic diseases was reviewed. 4 The authors found that ILIB application can decrease the levels of proinflammatory cytokines and oxidative stress and foster overall benefits for the patient. Among the challenges faced by the authors was a difficult comparison of results due to varied systemic conditions, differences in sites of irradiation (coronary artery, cubital vein, or large veins of the upper limb), variances in laser parameters, and protocol applications. 4
Considering the tendency of patients to adhere better to less invasive approaches, researchers are working to building up scientific evidence on the effects and benefits of using transcutaneous and transmucosal vascular irradiation. Preclinical models indicate that PBM of blood vessels performed through transcutaneous irradiation of the caudal artery in rats was suggested to improve systemic inflammation in acute lung injury, 15 and induce beneficial hemodynamic changes in spontaneously hypertensive animals. 16 As translatable approaches for these findings, different groups published protocols in animals using irradiation of the auricular artery, 17 and in humans, investigating irradiation of the radial artery and sublingual region. 11,18 Accordingly, a recent randomized clinical trial probed the effects of transcutaneous irradiation of radial artery to relieve pain and improve the quality of life in individuals with diabetic neuropathy. This study demonstrated that patients who were subjected to 3 stages of 10 daily applications of red laser (100 mW, 660–10 nm, 30 min) on the skin over the radial artery exhibited a 60% improvement in the pain sensation, ∼50% increase in their functional capacity, and ∼30% improvement in their mental health, among other parameters. 10 Likewise, promising clinical trials are ongoing to elucidate the effects of transmucosal blood photobiomodulation (BPBM) in patients with multiple sclerosis 18 and hypertension. 19
Unfortunately, besides the lack of standardization as for dosimetric parameters, nonexistence of consistent nomenclature is hampering a straightforward access to the research results. Currently, different terms have been used to designate irradiation of a specific vessel or group of vessels to obtain systemic benefits for the patient. The term systemic PBM can suggest full-body irradiation, as used in cancer conditioning protocols; however, this is not the case. Further, the term ILIB has also been applied for intravascular irradiation with low level laser sources that are delivered through a catheter. Thus, derivations of the term to accommodate the description of noninvasive procedures, such as “modified ILIB,” “new ILIB,” or “systemic photobiomodulation,” have been used, inducing to misleading interpretations. We think it is time to have a more specific nomenclature for noninvasive procedures that are designed to irradiate blood cells and vasculature targeting to obtain systemic effects. The term vascular photobiomodulation (VPBM) seems to be the most appropriate to encompass different light sources and varied anatomical sites, that is, transmucosal or transcutaneous, radial or sublingual arteries, etc.
Yet, nomenclature is not the only issue. Although current studies and literature reviews have moved our knowledge beyond the point of naive interpretation of overall metabolic improvements as a mere placebo effect, we still have a long way to go. We must (1) understand the mechanisms of action of this type of PBM, (2) determine potential risks, (3) define optimal protocols while working to collaborate with industry partners to develop new reliable wearable technologies for patients' use, and (4) align patients' and clinicians' expectations as for the outcomes. On the researchers' side, there are many questions that remain to be addressed. Some of these include what are the effects of skin color and body index mass in light scattering and final outcomes of transcutaneous applications? How long the potential benefits of the blood irradiation will last? What can be the potential adverse effects of an overstimulation? Do the effects come mainly from activation of specific leukocytes subtypes, red blood cells, endothelial cells, or pericytes? What is delaying the use organs-on-a-chip platforms to study the mechanisms of BPBM and VPBM? Is it safe to perform BPBM in cancer patients—either under treatment or after them being cured? If yes, how long is it necessary to wait before applying BPBM? What are the desirable characteristics of the next generation of wearable devices?
When it comes to VPBM, we must not be afraid of asking difficult questions that will change current paradigms and create change in as many levels as possible. As Marie Curie once said, “Nothing in life is to be feared, it is only to be understood. Now is the time to understand more, so that we may fear less.”